chr1-45332574-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001048174.2(MUTYH):c.606G>A(p.Gln202=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000248 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
MUTYH
NM_001048174.2 splice_region, synonymous
NM_001048174.2 splice_region, synonymous
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.83
Genes affected
MUTYH (HGNC:7527): (mutY DNA glycosylase) This gene encodes a DNA glycosylase involved in oxidative DNA damage repair. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a major oxidatively damaged DNA lesion. The protein is localized to the nucleus and mitochondria. This gene product is thought to play a role in signaling apoptosis by the introduction of single-strand breaks following oxidative damage. Mutations in this gene result in heritable predisposition to colorectal cancer, termed MUTYH-associated polyposis (MAP). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
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Very rare variant in population databases, with high coverage;
PP3
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Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
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Variant 1-45332574-C-T is Pathogenic according to our data. Variant chr1-45332574-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 481804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-45332574-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MUTYH | NM_001128425.2 | c.690G>A | p.Gln230= | splice_region_variant, synonymous_variant | 8/16 | ENST00000710952.2 | |
MUTYH | NM_001048174.2 | c.606G>A | p.Gln202= | splice_region_variant, synonymous_variant | 8/16 | ENST00000456914.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MUTYH | ENST00000710952.2 | c.690G>A | p.Gln230= | splice_region_variant, synonymous_variant | 8/16 | NM_001128425.2 | |||
MUTYH | ENST00000456914.7 | c.606G>A | p.Gln202= | splice_region_variant, synonymous_variant | 8/16 | 1 | NM_001048174.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251322Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135874
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461800Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2AN XY: 727214
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 29, 2024 | The c.690G>A pathogenic mutation (also known as p.Q230Q), located in coding exon 8 of the MUTYH gene, results from a G to A substitution at nucleotide position 690. This nucleotide substitution does not change the glutamine at codon 230. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported as compound heterozygous in individuals with colorectal polyposis; furthermore, this mutation has been shown to result in aberrant splicing with exon 8 skipping by RNA studies (Ambry internal data; Vogt S et al. Gastroenterology 2009 Dec; 137(6):1976-85.e1-10; Dallosso AR et al. Gut 2008 Sep; 57(9):1252-5). Of note, this mutation is also designated as c.681G>A in the published literature. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 29, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 28, 2023 | This synonymous variant does not change the amino acid sequence of the MUTYH protein, but it causes a G to A substitution at the last nucleotide position of exon 8 of the MUTYH gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has shown that this variant (also known as c.681G>A in the literature) causes skipping of exon 8 in the MUTYH transcript (PMID: 18515411). This variant has been reported in the compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID:18515411, 19032956, 19732775, 25559809). This variant has also been identified in 1/251322 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate abnormal splicing resulting in skipping of exon 8 (Dallosso et al., 2008); In silico analysis supports that this variant may damage or destroy the splice donor site and impact gene splicing; This variant is associated with the following publications: (PMID: 19032956, 19732775, 19394335, 23212176, 25525159, 18515411, 25559809, 34704405) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 27, 2018 | - - |
Familial adenomatous polyposis 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This synonymous variant does not change the amino acid sequence of the MUTYH protein, but it causes a G to A substitution at the last nucleotide position of exon 8 of the MUTYH gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. An RNA study has shown that this variant (also known as c.681G>A in the literature) causes skipping of exon 8 in the MUTYH transcript (PMID: 18515411). This variant has been reported in the compound heterozygous state in individuals affected with MUTYH-associated polyposis (PMID:18515411, 19032956, 19732775, 25559809). This variant has also been identified in 1/251322 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MUTYH function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change affects codon 230 of the MUTYH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MUTYH protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199989617, gnomAD 0.0009%). This variant has been observed in individual(s) with MUTYH-associated polyposis (PMID: 19732775, 25559809). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.681G>A. ClinVar contains an entry for this variant (Variation ID: 481804). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 18515411). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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Calibrated prediction
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Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at